0021-972X/80/5006-1089$02.

00/0
Journal of Clinical Endocrinology and Metabolism Vol. 50, No. 6
Copyright © 1980 by The Endocrine Society Printed in U.S.A.

Evolution of Toxicity in Solitary Nontoxic Autonomously

Functioning Thyroid Nodules
JOEL I. HAMBURGER
20905 Greenfield, Southfield, Michigan 48075

ABSTRACT. Between 1961 and 1979, 349 patients with auton-
omously functioning thyroid nodules (AFTN) were seen. There
were 287 nontoxic and 62 toxic lesions. Toxic lesions were seen
in 56.5% of AFTN patients over 60 yr of age but in only 12.5% of
the younger patients. The female to male ratio was 14.9:1 for
nontoxic AFTN patients but only 5.9:1 for toxic AFTN patients.
The proportion of toxic AFTN in patients less than 20 yr old
(13.8%) was not significantly different from that in patients 20-
60 yr old (12.7%). T3 toxicosis was observed in 46% of those
patients with hyperthyroidism. All but 4 of the toxic AFTN
measured 3 cm in diameter or larger. AFTN 3 cm or larger were
more than twice as common in patients 40 yr or older than in
younger patients. Of 159 untreated nontoxic AFTN patients, 14
became toxic within 1-6 yr. One patient in 5 with a nontoxic
AFTN 3 cm or larger developed toxicity. (J Clin Endocrinol
Metab 50: 1089, 1980)

S OLITARY autonomously functioning thyroid nod-

ules (AFTN) are discrete thyroid lesions, not de-
pendent upon pituitary stimulation for either function or
the author's experience, in which only 1 toxic AFTN is
seen for every 50 patients with toxic diffuse goiter.
Because of the infrequency of AFTN and the prefer-
growth. The availability of radioactive iodine permitted ence by many physicians to ablate nontoxic AFTN pro-
Cope et al. to demonstrate, in vitro, an inverse relation- phylactically, there is controversy with respect to the
ship between the functional activity of the AFTN and following issues. (1) How often and how rapidly do non-
the remaining extranodular thyroid tissue (1). These toxic AFTN progress to toxicity? In a previous publica-
observations were confirmed by in vivo studies using tion, this author (5) has provided support for the limited
hand [Dobyns et al. (2)] and mechanical [Sheline and published data suggesting that this progression is rare (6,
McCormack (3) and Miller and Hamburger (4)] radio- 7,12,13). (2) What proportion of toxic AFTN selectively
nuclide detection devices. secrete an excess of T3? In an earlier report, I suggested
Laboratory criteria for the diagnosis of AFTN are well with limited data, that T3 toxicosis was the exception in
established (4, 5). These include persistent nodular func- AFTN (5). (3) Do toxic AFTN tend to be larger and
tion (autonomous function) in spite of the administration occur more often in older patients? This concept has
of normally suppressive doses of thyroid hormone and been suggested by some (5, 14, 15) but challenged by
the preferential responsiveness of suppressed extranod- others (6, 7). (4) Are AFTN, especially toxic AFTN, rare
ular thyroid tissue to parenteral TSH. Wider application in children, as previous reports suggest (16, 17)? The
of these criteria has permitted the diagnosis of smaller present report provides data from 349 patients with
AFTN and the appreciation that nontoxic AFTN are AFTN to help clarify these questions.
much more common than the toxic form (5-7).
Nevertheless, the solitary AFTN is uncommon in the Materials and Methods
United States. Only 0.9% of patients referred to the
author's laboratory for thyroid evaluations had this dis- Between 1961 and 1979, 39,487 patients have been referred
ease, a frequency comparable to the 1% incidence re- for diagnosis and management of thyroid problems to the
ported by Silverstein et al. (6). Somewhat higher inci- author's clinic (Southfield, MI). Diagnostic methods for the
dences of 2.4% and 6% have been reported from Brazil confirmation of the diagnosis of AFTN have been described in
detail in earlier publications (4, 5). Criteria for a diagnosis of
(8, 9), and 9% has been reported from Holland (10). In
AFTN were met by 349 patients (0.9%). Five percent of patients
Switzerland, one third of all patients with hyperthyroid- with solitary nodules had AFTN.
ism have toxic AFTN (11). This contrasts sharply with Thyroid nodule size was estimated by palpation in conjunc-
Received November 9,1979.
tion with thyroid imaging. AFTN sizes cited throughout the
Address requests for reprints to: Dr. Joel I. Hamburger, 20905 paper refer to average diameter in centimeters.
Greenfield, Suite 300, Southfield, Michigan 48075. Standard methods were employed for laboratory confirma-

1089

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1090 HAMBURGER JCE & M '
Vol50«

tion of the clinical diagnosis of thyroid function. Patients were highly significant difference (x2 analysis, P < 0.001).
not considered hyperthyroid in the absence of clinical findings. These data indicate that hyperthyroidism occurs more
Methods for the assessment of serum T 4 concentrations often in elderly patients with AFTN, and that a greater
changed over the 18-yr period of study. Thus, T4 was measured proportion of males with AFTN have toxic lesions. There
by the PBI, column chromatography, displacement, or RIA
method. The serum T3 concentration was measured by RIA
were 4 patients less than 13 yr old and 29 (8.3%) less than
using the T3 (RIA) PEG kit method from Abbott Laboratories 20 yr old. Thus, young people with AFTN are not rzje.
(Chicago, IL). The normal range for our laboratory is 80-220 Furthermore, the proportion of toxic AFTN in patients
ng/dl. less than 20 yr old is as great as that in those between
Ablative therapy (surgery or radioactive iodine) was advised the ages of 20-60 yr.
for all patients with toxic AFTN and, in the early years, for For 35 of the 62 clinically hyperthyroid patients, meas-
many nontoxic AFTN as well, particularly those in older pa- urements of serum concentrations of both T3 and T4 were
tients or for whom thyroid function tests were at the upper available. In 16 patients both hormones were elevated,
level of the normal range. Thus, between 1961 and 1970, 24 16 had elevations only of T3, and 3 patients had elevations
(26.7%) of 90 AFTN were subjected to prophylactic ablation.
only of T4. However, there were an additional 7 patients,
However, from 1971 to 1979 prophylactic ablation was more
selectively employed, and only 12 (4.6%) of 259 AFTN were so
with AFTN between 2.5-3.5 cm in diameter, who ware
treated. considered to have borderline biochemical hyperthyrc id-
ism on the basis of blunted TRH tests and serum T 3
Results concentrations between 200-220 ng/dl. One patient also
Table 1 gives the age and sex distribution for the 349 had a borderline high serum T4 concentration. Finally, 1
AFTN patients. There were 62 (17.8%) toxic AFTN sub- patient, initially with mild T3 toxicosis, developed hy-
jects and 287 (82.2%) nontoxic AFTN subjects. The toxic persecretion of both T 3 and T4 1 yr later.
group includes AFTN in patients with clinical and bio- Table 2 presents a correlation of age and nodule size
chemical findings of hyperthyroidism at the initial eval- for toxic and nontoxic AFTN. Of 213 nodules up to 2.5
uation as well as those who developed these findings cm in diameter, only 4 (1.9%) were toxic (all of them were
subsequently. The age cited is the age at which toxicity 2.5 cm in diameter), whereas the remaining 136 larger
became evident. Of the 287 euthyroid patients, 138 (48%) nodules, 58 (42.6%) were toxic. This is a highly significant
were 40 yr old or older, compared to 45 (72.6%) of 62 difference (x2 analysis, P < 0.001). In 183 patients 4C yr
hyperthyroid patients. Of the 46 AFTN in patients 60 yr and older there were 84 (45.9%) nodules 3 cm or larger,
or older, 26 (56.5%) were toxic, whereas only 36 (12.5%) whereas in 266 patients younger than 40 yr there were
of the 289 patients younger than 60 yr had toxic AFTN. only 52 (19.5%) nodules which were that large. This :.s a
This is a highly significant difference (x2 analysis, P < highly significant difference (x2 analysis, P < 0.001). All
0.001). patients with toxic AFTN smaller than 3 cm in diameter
were less than 50 yr old, and of 13 patients with toxic
There were 27 (7.7%) males and 322 (92.3%) females
AFTN 5 cm or larger, 10 (76.9%) were in patients 50 yr
among the 349 AFTN patients. The female to male ratio
old or older. Thus, older patients tend to have larger
for nontoxic AFTN was 14.9:1, but the ratio for toxic
toxic AFTN. A final observation is that two thirds, of
AFTN was only 5.9:1. The proportion of toxic AFTN in
males with nontoxic AFTN had nodules 3 cm or larger,
males was 33%, but was only 16.5% in females. This is a
whereas only 16% of females had these larger lesions.
TABLE 1. Age and sex distribution of toxic and nontoxic AFTN Table 3 presents a correlation of the function of un-
treated AFTN after varying periods of follow-up for the
Females with Males with various age groups. Of 142 patients followed up to 6 yr,
No. of 14 (10%) developed toxicity, whereas none of the 17
Age (yr) pa- Non- _, . Non- _, . % Toxic patients followed for 7-15 yr developed toxicity. The
,. A , . Toxic A . Toxic
tients toxic toxic
AFTN AFTN
tendency to employ prophylactic surgical or radioactive
iodine ablation of large AFTN before 1971 probably
11-19 29 24 4 1 13.8 explains the infrequency with which toxicity developed
20-29 68 60° 5 2 8.8
30-39 69 60 7 2 10.1
in this latter group of patients which was followed for the
40-49 70 59 7 4a 10.0 longest period of time. Of 14 patients who developed
50-59 66 48" 11 6 18.2 toxicity within 6 yr, 9 (64.3%) were less than 40 yr old.
60-69 35 14 13 3 51.4 Ten (20%) of 50 patients with nontoxic AFTN 3 cm or
70+ 12 4 6 0 66.7 larger developed toxicity, whereas toxicity occurred in
only 4 (5.7%) of 70 nontoxic AFTN 2-2.5 cm and in one
Total 349 269 53 18 17.8
a
of 39 smaller nontoxic AFTN. All 14 patients were
One patient in each of these three age-sex groups had an episode women.
of transient toxicity resulting from acute hemorrhagic infarction.

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 EVOLUTION OF TOXICITY IN AUTONOMOUS THYROID NODULES 1091

TABLE 2. Correlation of age and nodule size for toxic and nontoxic in the previously suppressed extranodular thyroid tissue,
AFTN
and the patients were clinically and biochemically euthy-
Nodule size (cm) roid (18).

Age <2 2-2.5 3-4.5 5+ Discussion

(yr)
_ . Non- _ . Non- ^ . Non- ~ . Non-
Toxic . . Toxic . Toxic , . Toxic , .
The AFTN is an unusual thyroid lesion in the United
toxic toxic toxic toxic States, being present in only about 1% of patients referred
11-19 0 9 1 11 3 5 0 0 for thyroid evaluation and 5% of those with solitary or
20-29 0 15 1 30 4 16 1 1 dominant thyroid nodules. Modern diagnostic methods
30-39 0 19 1 27 5 16 1 0 have permitted the identification of many small AFTN,
40-49 0 16 1 31 5 16 1 0
50-59 0 11 0 26 10 15 3 2
lesions which are almost never toxic. The unusual pre-
60-69 0 4 0 8 14 4 4 1 dominance of women over men (by more than 10 to 1) is
70+ 0 0 0 2 4 2 3 0 most striking in those series which includes primarily
small nontoxic AFTN (5, 7). The sex ratio for the toxic
Total 0 64 4 145 45 74 13 4 AFTN (5 to 1 in favor of females) more nearly resembles
that seen with hyperthyroidism of the Graves' type.
TABLE 3. Correlation of function of untreated AFTN with age after
varying follow-up periods
Although AFTN were distributed about equally in
patients older and younger than 40 yr, three fourths of
Duration of follow-up (yr) the toxic AFTN were seen in the older patients. Further-
more, more than half of the patients 60 years of age and
Age 1-2 3-4 5-6 7-15 older were hyperthyroid. The high frequency of toxic
(yr)
Non- _, . Non- _ . Non- . Non- _ .
AFTN in older patients has been reported previously (5,
, . Toxic , . Toxic , . Toxic , . Toxic 7, 14). The observation that four patients less than 20 yr
toxic toxic toxic toxic
old had toxic AFTN and that the proportion of AFTN
11-19 6 2 3 1 0 0 1 0
20-29 18 3 8 0 3 0 7 0 which are toxic in these young patients is not significantly
30-39 16 2 8 0 4 1 3 0 different from that observed in all age groups younger
40-49 16 0 10 0 4 0 3 0 than 60 yr suggest that AFTN may be more common in
50-59 9 1 7 1 6 1 2 0 young people than reports in the pediatric literature
60+ 5 1 4 0 1 1 1 0
might indicate (16, 17).
Total 70 9 40 2 18 3 17 0 Selective excess T 3 secretion has been reported in both
nontoxic AFTN (19) and toxic AFTN (14, 20, 21). How-
ever, the proportion of AFTN which exhibit T3 toxicosis
Table 4 shows the changes in nodule size observed in has not been well established; T3 RIA has been generally
the 159 patients followed from 1-15 yr. An increase in
nodule size of at least 1 cm was seen in only 15 (9.4%) TABLE 4. Correlation of change in nodule size and duration of follow-
patients. For 4 of these patients the growth was accom- up for nontoxic AFTN patients
panied by the development of toxicity. Two AFTN en-
Duration of follow-up
larged and became less functional on scintiscan, probably
because of degeneration. There was no substantial Change in nodule size (yr)
change in size (greater than 0.5 cm) for 136 AFTN (86%). 1-2 3-4 5-6 7-15 Total
Nevertheless, 10 of these nodules became toxic. Loss of fl cm or more and became 4 0 0 0 4
nodule function was observed in 4 stable nodules on toxic
follow-up imaging, again probably because of degenera- f 1 cm or more, euthyroid 3 1 0 5 9
1—1

tion. Six nodules (3.8%) decreased in size. For 4 of these fl cm or more, euthyroid, de- 1 0 0 2
nodules, imaging revealed a loss of nodular function and generation
No change 60 37 14 11 122
an increased activity in the extranodular tissue. A tran- No change, degeneration 3 1 0 0 4
sient increase in nodule size associated with hyperthy- No change, toxic 5 2 3 0 10
roidism was observed in 3 patients; this presumably J,l cm or more 1 1 3 1 6
resulted from acute hemorrhagic infarction. For 2 of fl cm, transient toxicity, then 2n 0 0 0 2
these patients, needle aspiration produced prompt regres- [1 cm
sion of the nodules and relief of pain. By 6 weeks to 3 Total 79 42 21 17 159
months after the acute phase, all 3 nodules were substan-
f, Nodule increased in size; J,, nodule decreased in size.
tially smaller than at the time of the initial evaluation. " One additional patient presented with acute nodular enlargement
In addition, there was recovery of function on scintiscan and T3 toxicosis, both of which subsided spontaneously.

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1092 HAMBURGER JCE & M • 1980
Vol 50 • No 6

available only in the past 7-8 yr, AFTN are not common TABLE 5. Results of follow-up of untreated patients with nontoxic
lesions, and toxic AFTN are even less common. Prophy- AFTN
lactic ablation of nontoxic AFTN, a common practice, No. Duration of fol- Hy- Border-
has also served to limit experience on this point. An of low-up (yr) per- line hy-
Author Country Yr
earlier report (5) included only two patients with toxic pa- thy- per-thy-
AFTN for whom serum T3 data were available. One of tients Range Mean roid roid
the two had T3 toxicosis. In that report a larger number McCormack U.S. 1967 14 2.5-8.5 4.8 1 0
of nontoxic AFTN had been studied, and the T3 and T4 Silverstein U.S. 1967 9 2-7 4 0 1)
Miller U.S. 1968 15 1-7 3 0 )
levels generally paralleled one another. Thus, it was Burman U.S. 1974 48 '/3-11.3 2 0 0
incorrectly concluded that T3 toxicosis was probably the Blum U.S. 1975 13 ? 4 3
exception. The present results, indicating that 46% of Hamburger U.S. 1975 51 1-12 3.3 0 D
patients with toxic AFTN had T3 toxicosis, serve to Hamburger U.S. Current 159 1-15 3.5 14 6
correct this error. The additional seven patients with Lobo Brazil 1965 5 V4-3 1 1
Wiener Nether- 1979 58 1-11.8 4 6 1
high normal T3 values, blunted TRH responses, and lands
relatively large AFTN may represent a transition stage
in the conversion of a nontoxic to a toxic AFTN. Indeed,
one patient who ultimately developed hypersecretion of Most of the earlier papers dealt with small numbers of
T3 and T4 had presented 1 yr earlier with mild T 3 toxi- patients, only a few of whom were followed for more than
cosis. The incidence of T3 toxicosis in this report is 1 or 2 yr. Up to 1975 there were 146 patients reported
substantially more than the 20% reported by Blum et al. from the United States, of whom only 5 developed hy-
in a somewhat smaller group of patients (14). However, perthyroidism. Four of the 5 patients were from the
for four of Blum's euthyroid patients serum T3 results report of Blum et al. (14) and 1 of these patients devel-
were not available. In any event, it is clear that the oped a transient episode of hyperthyroidism induced by
incidence of T3 toxicosis is high enough to indicate that iodide in a radiographic contrast medium. The recent
the T 3 assay is an essential component in the diagnostic report of Wiener and DeVries (10) showed that 6 of 58
workup of patients with AFTN. nontoxic AFTN became toxic within 1-11.8 yr. Wiener
Although it has been repeatedly observed that toxic suggested that patients less than 40 yr old progress :!rom
AFTN are usually 3 cm or larger (5, 10, 14, 15, 21), this nontoxic to toxic AFTN more rapidly than older patients.
concept has been challenged by 2 authors on the basis of Since this report comes from Europe, it may not be useful
a combined experience with 3 patients with toxic AFTN for comparison with studies on patients in the United
(6, 7). One of these 3 patients had a toxic AFTN esti- States because the incidence of AFTN is much higher in
mated to be only 1.5 cm in diameter. The author acknowl- Europe (11). The small number of patients described
edged that size estimates are subject to doubt (7), and with a transition from nontoxic to toxic AFTN in ejirlier
this fact might present a problem in comparing size reports from the United States does not seem to be the
estimates in reports from different centers. Nevertheless, result of the patients not having been followed long
experienced examiners can easily detect size changes of enough. For 9 of 14 patients who progressed to toxicity
0.5-1.0 cm. None of the 62 toxic AFTN reported here in the present series, the change was documented within
were less than 2.5 cm in diameter, and the same can be 2 yr from the initial presentation, and all 14 transitions
said for a combined series of 49 patients from 2 other took place within 6 yr. Identification of patients demon-
reports in which nodule size is provided (14, 15). Most strating this transition seems to be dependent upon fol-
(93.5%) of the toxic AFTN in the present series were 3 lowing a large number of patients and not subjecting
cm or larger, as were all of the toxic AFTN in Blum's patients with high normal levels of thyroid function to
series, and 84% of the toxic AFTN in the series reported prophylactic ablation. Prophylactic ablation had been a
by Molnar et al. (15). In none of these 3 series were any common practice in the author's clinic between 1961 and
toxic AFTN smaller than 2.5 cm. This suggests that the 1970. This has been done much less frequently since
small toxic AFTN reported by Gurman et al. (7) was 1971; it was hoped that observing a sizeable number of
exceptional. As a final point, the thyroid function tests in nontoxic AFTN would permit a determination of how
the case of Burman et al. were only at the upper level of often these lesions progress to toxicity. In the absence of
normal. information on this point, therapeutic recommendations
There have been 7 previous publications from other for nontoxic AFTN have been determined by personal
clinics which included data on the frequency and rapidity preferences or, perhaps, by anecdotal experience. This
with which nontoxic AFTN progress to toxicity. Table 5 need no longer be the case. It can be estimated now that
compares the findings in these reports with those from about 1 patient in 5 with a nontoxic AFTN 3 cm or larger
both the current series and an earlier publication (5). will develop hyperthyroidism within 1-6 yr. For smaller

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 EVOLUTION OF TOXICITY IN AUTONOMOUS THYROID NODULES 1093

nodules the risk is considerably less. This information Autonomous thyroid nodules. I. A clinical classification and the use
of a diagnostic index, J Nucl Med 13: 733, 1972.
offers support for a recommendation of prophylactic
10. Wiener, J. D., and A. A. DeVries, On the natural history of Plum-
ablation for large AFTN, especially if the secretory activ- mer's disease, Clin Nucl Med 4: 181, 1979.
ity is at a high normal level and the patient is 50 yr of 11. Horst, W., H. Rosier, C. Schneider, and A. Labhart, Three hundred
age or older, when tolerance for hyperthyroidism may be six cases of toxic adenoma, J Nucl Med 8: 515, 1967.
12. McCormack, K. R., and G. E. Sheline, Long-term studies of solitary
reduced. autonomous thyroid nodules, J Nucl Med 8: 701, 1967.
13. Miller, J. M., and M. A. Block, The autonomous functioning thyroid
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1171, 1949. 16. Granoff, A. B., and J. M. Hershman, Suppression of pituitary TSH
3. Sheline, G. E., and K. McCormack, Solitary hyperfunctioning thy- in a child with a hyperfunctioning thyroid nodule, J Pediatr 90:
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